Gabriela Voskerician

Biocompatibility and biofouling of MEMS drug delivery devices

The biocompatibility and biofouling of the microfabrication materials for a MEMS drug delivery device have been evaluated. The in vivo inflammatory and wound healing response of MEMS drug delivery component materials, metallic gold, silicon nitride, silicon dioxide, silicon, and SU-8(TM) photoresist, were evaluated using the cage implant system. Materials, placed into stainless-steel cages, were implanted subcutaneously in a rodent model. Exudates within the cage were sampled at 4, 7, 14, and 21 days, representative of the stages of the inflammatory response, and leukocyte concentrations (leukocytes/microl) were measured. Overall, the inflammatory responses elicited by these materials were not significantly different than those for the empty cage controls over the duration of the study. The material surface cell density (macrophages or foreign body giant cells, FBGCs), an indicator of in vivo biofouling, was determined by scanning electron microscopy of materials explanted at 4, 7, 14, and 21 days. The adherent cellular density of gold, silicon nitride, silicon dioxide, and SU-8(TM) were comparable and statistically less (p<0.05) than silicon. These analyses identified the MEMS component materials, gold, silicon nitride, silicon dioxide, SU-8(TM), and silicon as biocompatible, with gold, silicon nitride, silicon dioxide, and SU-8(TM) showing reduced biofouling.

Biomaterial adherent macrophage apoptosis is increased by hydrophilic and anionic substrates in vivo

An in vivo rat cage implant system was used to identify potential surface chemistries that prevent failure of implanted biomedical devices and prostheses by limiting monocyte adhesion and macrophage fusion into foreign-body giant cells while inducing adherent-macrophage apoptosis. Hydrophobic, hydrophilic, anionic, and cationic surfaces were used for implantation. Analysis of the exudate surrounding the materials revealed no differences between surfaces in the types or levels of cells present. Conversely, the proportion of adherent cells undergoing apoptosis was increased significantly on anionic and hydrophilic surfaces (46 ± 3.7 and 57 ± 5.0%, respectively) when compared with the polyethylene terephthalate base surface. Additionally, hydrophilic and anionic substrates provided decreased rates of monocyte/macrophage adhesion and fusion. These studies demonstrate that biomaterial-adherent cells undergo material-dependent apoptosis in vivo, rendering potentially harmful macrophages nonfunctional while the surrounding environment of the implant remains unaffected.

Differential degradation rates in vivo and in vitro of biocompatible poly(lactic acid) and poly(glycolic acid) homo- and co-polymers for a polymeric drug-delivery microchip.

The biocompatibility and biodegradation rate of component materials are critical when designing a drug-delivery device. The degradation products and rate of degradation may play important roles in determining the local cellular response to the implanted material. In this study, we investigated the biocompatibility and relative biodegradation rates of PLA, PGA and two poly(lactic-co-glycolic acid) (PLGA) polymers of 50 : 50 mol ratio, thin-film component materials of a drug-delivery microchip developed in our laboratory. The in vivo biocompatibility and both in vivo and in vitro degradation of these materials were characterized using several techniques. Total leukocyte concentration measurements showed normal acute and chronic inflammatory responses to the PGA and low-molecular-weight PLGA that resolved by 21 days, while the normal inflammatory responses to the PLA and high-molecular-weight PLGA were resolved but at slower rates up to 21 days. These results were paralleled by thickness measurements of fibrous capsules surrounding the implants, which showed greater maturation of the capsules for the more rapidly degrading materials after 21 days, but less mature capsules of sustained thicknesses for the PLA and high-molecular-weight PLGA up to 49 days. Gel-permeation chromatography of residual polymer samples confirmed classification of the materials as rapidly or slowly degrading. These materials showed thinner fibrous capsules than have been reported for other materials by our laboratory and have suitable biocompatibility and biodegradation rates for an implantable drug-delivery device.

In vivo inflammatory and wound healing effects of gold electrode voltammetry for MEMS micro-reservoir drug delivery device

The in vivo biocompatibility and biofouling of gold electrodes for a microelectromechanical systems drug delivery device were investigated in a rodent model. The role of the applied voltage and gold electrolysis products in modulating the inflammatory response (biocompatibility), and the temporal adhesion of cellular populations onto macroscopic gold film electrodes (biofouling) were analyzed in reference to two controls, devices to which voltage was not applied (uncorroded) or voltage was applied to inert platinum electrodes (electrical controls). Voltammetry was applied to the gold surfaces once (day 4, 7, 14, 21, 28, 35, 42, or 49), while voltage of identical magnitude was applied to the electrical controls. An inflammatory response characterized by a rapid decrease of leukocyte concentration to control levels was observed 48 h following voltage application with no significant cell concentration difference (p>0.05) between the corroded devices and electrical controls. The histological evaluation of the direct implant fibrous capsule showed comparable thickness of voltage applied and control specimens. The gold corrosion peak current showed no significant difference (p>0.05) among peak values at all time points. It was concluded that gold electrode corrosion was biocompatible and its electrochemical performance was not hindered by fibrous capsule formation.

Electrochemical characterization and in vivo biocompatibility of a thick-film printed sensor for continuous in vivo monitoring

This paper assessed the material biocompatibility and investigated the temporal modulation in electrochemical performance of printed thick-film electrochemical sensing devices (ESDs) that can serve as the basis of various enzymatic sensor in detecting an electrochemically potent species. The sensors were placed in phosphate buffered saline (PBS), human serum, or implanted subcutaneously in rats, free or in stainless steel cages. The exudate collection allowed the evaluation of inflammatory cell populations, up to 21 days. The ferrous/ferric redox electrode reactions were used to assess the electrode elements performance for up to 49 days. Following testing, scanning electron microscopy (SEM) evaluated cell surface adhesion, while fibrous capsules were examined by histology. It was determined that the exudates leukocyte concentration due to the presence of sensors was comparable to the empty cage controls. For the length of the study, the sensors functionality appeared not to be influenced by the in vivo environment, when tested ex vivo, without the surrounding fibrous capsule. Surface imaging (SEM) indicated temporal focal dissolution of the Ag/AgCl electrodes with no apparent local toxicity. We concluded that the ESDs were biocompatible and their ex vivo functionality was not lost when maintained in vivo for up to 49 days.

High molecular weight kininogen inhibition of endothelial cell function on biomaterials

Synthetic vascular grafts implanted into humans fail to develop a complete endothelial lining. In previous studies, we have shown that high-molecular-weight kininogens (HMWK) adsorb to the surfaces of biomaterials. In addition, it has been demonstrated that these proteins modulate cellular function. In the present study, we report on the adhesion and proliferation of human umbilical-vein endothelial cells (HUVEC) on tissue culture polystyrene, glass, polyurethane, and Mylar(trade mark) surfaces coated with human HMWK, either single-chain HMWK (SC-HMWK) or double-chain HMWK (DC-HMWK). Surfaces coated with fibronectin served as a positive control for these experiments. Parallel experiments were performed in which HUVEC were allowed to migrate from crosslinked dextran microcarrier beads (Cytodex 2) onto HMWK-coated surfaces. Our results indicate that HMWK-coated surfaces inhibit endothelial cell adhesion, proliferation, and migration at 24 and 72 h, and this inhibition is concentration dependent. To determine a potential mechanism for this inhibitory phenomenon, cells were stained for cytoskeletal actin filaments using rhodamine-phalloidin. Endothelial cells on HMWK-coated surfaces displayed F-actin filament reorganization/disassembly, characterized by the absence of peripheral actin bands in focal adhesion contacts. We conclude that HMWK inhibit endothelial cell adhesion, proliferation, and migration on a variety of biomaterial surfaces. This inhibitory effect may play a role in promoting the lack of endothelialization in synthetic vascular grafts, which is thought to play a significant role in the failure of these devices.

Design considerations of an analytic intelligence for predicting the efficacy of tissue engineered composites

Graphical Abstract

A manifesto to action: trickle or trailblazing in translational research?

Consistently, every year, more than half of the submissions to the Journal of Materials Science: Materials in Medicine flag the ‘‘potential’’ of the discussed innovation for translation into a bedside solution. Yet, even beyond the confines of JMSM, very few groups advance their research beyond a small animal model biocompatibility validation. As a journal and as a research community, we need to look more closely at our capacity to translate discoveries into viable clinical solutions. Where are the barriers and how can they be eliminated? The Editors would like to encourage an open discussion and assessment of current biomedical research practice. To ensure uniformity, translational research is understood as defined by the National Institutes of Health (NIH), i.e., ‘‘the movement of discoveries in basic research to application at the clinical level’’. Recently I had an opportunity to discuss the state of translational research with Professor James M. Anderson, MD, PhD [Case Western Reserve University, USA], and Professor Yasuhiko Tabata, MD, PhD, D. Pharm. [University of Kyoto, Japan]. Some of their thoughts are incorporated below, and suggest that whether translational research is trickling or reshaping the biomedical research landscape depends on who you ask. The primary barriers to bedside translation and adoption of biomedical research are often recognized to be: (1) operation within ‘‘silos’’ [no/limited communication/exchange]; (2) research abandoned/stagnant before the biocompatibility validation is completed; (3) operation within a product life-cycle vacuum [no early consideration towards critical product design parameters for reaching the bedside]. Are we operating under a silo syndrome? The answer seems to be ‘‘Yes!’’. While competition is a healthy practice, restricted or no communication as a result of competition [to publish or attract funding] will impact innovation. We tend to come together under one project goal only when we are forced/enticed by specific funding mechanisms. We challenge our readers to take a hard look at their track record: How many times have you actually pursued a collaboration in the absence of consortium project funding? The traditional scenario plays out as: we come together ? we put together the consortium ? the project (unfortunately) does not get funded ? we say ‘‘goodbye’’ only to return to our own silo. This is the behavior of someone in ‘‘survival mode.’’ As scientists, we need funding to survive, hence we try anything and everything, more often than not using a shotgun approach, hoping to find the ‘‘right’’ formula. The danger of the silo effect is highlighted by award-winning writer Gillian Tett’s most recent release ‘‘The Silo Effect’’ where she demonstrates the anti-innovation effect brought about by the of absence of collaboration and communication. Do we have a short attention span, changing research focus gears more often than we should? Again, the answer seems to be ‘‘Yes!’’. How many of us think beyond the 24 well plate biocompatibility validation? How many of us verify the actual potential of the innovation to reach bedside with a colleague clinician beyond a 15 min phone call or a five sentence e-mail? Preliminary findings are often discarded/abandoned to re-direct the focus towards the post-doc who just brought in some funding tied into a specific research goal. Even more disconcerting is the fact that some of us do not take the time to understand the most appropriate animal model selection and progression [and & Gabriela Voskerician gxv4@case.edu

The challenge of biocompatibility evaluation of biocomposites

The evaluation of biological response, i.e., biocompatibility, of biocomposites is complex, complicated and challenging. Biocompatibility studies of biocomposites present two major challenges: 1) identification of the overall biocompatibility (safety) of the biocomposite and identification of the contributions made by each of the distinct phases of the biocomposite structure at the tissue/biocomposite interface; and 2) surface characterization of the biocomposite structure where the distinct characteristics of each of the phases are appropriately and adequately characterized. The recent use of bioactive materials, tissue engineering, and nanotechnology in the development and/or utilization of biocomposites further enhance these challenges. This chapter focuses on the challenges that must be met in the future development of biocomposites.